Accomplishments for FY2010: 1) We have extended our experimental support for the conclusion that mammalian prions that cause a transmissible spongiform encephalopathy (TSE or prion disease) can be generated solely from bacterially expressed recombinant prion protein. This discovery provides the most compelling evidence so far for the potential protein-only prion hypothesis for the nature of the TSE infectious agent. However, the data leave open the likelihood that other molecules strongly enhance the infectious titers of pathological forms of prion protein. 2) We have studied the strain-dependent structures of prion seeded recombinant PrP fibrils. 3) We have extended our characterization of TSE strain-dependent differences in the interactions between prion protein and complement factors. 4) We have probed the effects of glycosylation and GPI-anchoring on the conformations of different strains of scrapie-prion protein by infrared spectroscopy. 5) We have studied cellular effects of nucleic acid binding to normal prion protein.